This invention relates to a new and useful process for resolving a racemic spiro-hydantoin compound into its optical antipodes. More particularly, it is concerned with a novel three-step process for preparing various optically-active asymmetric spiro-hydantoin compounds (including sorbinil), which are known to be of value in the medical control of certain chronic diabetic complications arising from diabetes mellitus. The invention also includes within its scope certain corresponding novel ureido compounds, which are used as intermediates in the aforesaid novel process.
In accordance with the prior art, it is now known that certain optical isomers of various asymmetric spiro-hydantoin compounds are useful as aldose reductase inhibitors and hence, of value in the treatment of certain chronic diabetic complications such as diabetic cataracts, neuropathy and retinopathy, etc. Included among these agents are such optically-active compounds as (4S)-(+)-6-fluoro-2,3-dihydro-spiro [4H-benzopyran-4,4'-imidazolidine]-2',-5'-dione (sorbinil), which is described and claimed by R. Sarges in U.S. Pat. No. 4,130,714 and (5'S)-3'-chloro-5',6',7',8'-tetrahydro-spiro [imidazolidine-4,5'-quinoline]-2,5-dione which is disclosed by C. A. Lipinski in Published European patent application No. 180,421 (published May 7, 1986).
In the past, these particular compounds (i.e., optical isomers) have been obtained by various means. For instance, sorbinil was first obtained after resolution of the corresponding d1-compound with 1-brucine and reported as d-6-fluoro-spiro[chroman-4,4'-imidazolidine]-2',5'-dione by R. Sarges in aforesaid U.S. Pat. No. 4,130,714. Later synthetic developments involved the use of asymmetric induction starting with a ketone precursor (viz., 6-fluoro-2,3-dihydro-4H-1-benzopyran-4-one) and optically-active (S)- .alpha.-methylbenzylamine in the presence of titanium tetrachloride, as reported by R. Sarges et al. in the Journal of Organic Chemistry, Vol. 47, p. 4081 (1982); while more recently, in U.S. Pat. No. 4,716,113 to F. J. Urban, there is described a multi-step process for preparing sorbinil, starting from 2-(4'-fluorophenoxy)ethyl bromide, wherein the enzyme .alpha.-chymotrypsin is employed to resolve the intermediate known as methyl 4-amino-6-fluorochroman-4-carboxylate into its respective optical antipodes prior to conversion to the desired spiro-hydantoin ring compound via treatment with an alkali metal cyanate in an acid medium.
In the search for improved methods of production in this particular area, little is known about the use of other methods of asymmetric induction, such as the reaction of an asymmetric isocyanate with the spiro-hydantoin ring system, etc., even though these methods have been briefly employed in the past with variable success in the field of heterocyclic chemistry when applied to other heterocyclic ring systems. For instance, in a paper by W. H. Pirkle et al., appearing in the Journal of Organic Chemistry, Vol. 49, p. 2433 (1984), there is described a method for resolving several chiral lactams by reacting said compounds with a chiral isocyanate, such as .alpha.-phenylethyl isocyanate, to afford the corresponding diastereomeric ureides that are then readily separable by means of chromatography on silica; the desired lactam enantiomers are thereafter retrieved from the separated ureides by means of hydrolysis.